PDB-7rw7: Crystal structure of human methionine adenosyltransferase 2A (MAT...

ID or keywords:

Entry

Database: PDB / ID: 7rw7

Title

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor Compound 9

Components

S-adenosylmethionine synthase isoform type-2

Keywords

TRANSFERASE/INHIBITOR / METHIONINE ADENOSYLTRANSFERASE / SAM / ALLOSTERIC INHIBITOR / TRANSFERASE / TRANSFERASE-INHIBITOR COMPLEX

Function / homology

Function and homology information

methionine adenosyltransferase complex / methionine adenosyltransferase / methionine adenosyltransferase activity / S-adenosylmethionine biosynthetic process / Methylation / protein heterooligomerization / cellular response to methionine / protein hexamerization / small molecule binding / positive regulation of TORC1 signaling ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.19 Å

Authors

Jin, L. / Padyana, A.K.

Funding support

1items

Citation

Journal: J.Med.Chem. / Year: 2022
Title: Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.
Authors: Li, M. / Konteatis, Z. / Nagaraja, N. / Chen, Y. / Zhou, S. / Ma, G. / Gross, S. / Marjon, K. / Hyer, M.L. / Mandley, E. / Lein, M. / Padyana, A.K. / Jin, L. / Tong, S. / Peters, R. / ...

History

Deposition	Aug 19, 2021	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Mar 23, 2022	Provider: repository / Type: Initial release
Revision 1.1	Mar 30, 2022	Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2	Apr 6, 2022	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3	Oct 18, 2023	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	7rw7.cif.gz	249 KB	Display	PDBx/mmCIF format
PDB format	pdb7rw7.ent.gz	161.6 KB	Display	PDB format
PDBx/mmJSON format	7rw7.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	7rw7_validation.pdf.gz	1 MB	Display	wwPDB validaton report
Full document	7rw7_full_validation.pdf.gz	1 MB	Display
Data in XML	7rw7_validation.xml.gz	25.6 KB	Display
Data in CIF	7rw7_validation.cif.gz	41.2 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/rw/7rw7 ftp://data.pdbj.org/pub/pdb/validation_reports/rw/7rw7	HTTPS FTP

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Related structure data

Related structure data	7rw5C 7rwgC 7rwhC 2p02S 7kcc C: citing same article (ref.) S: Starting model for refinement
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#139 - Jul 2011 DNA Methyltransferase similarity (1)

Deposited unit

A: S-adenosylmethionine synthase isoform type-2

hetero molecules

45.1 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: S-adenosylmethionine synthase isoform type-2

hetero molecules

A: S-adenosylmethionine synthase isoform type-2

hetero molecules

defined by author&software
Evidence: gel filtration
90.2 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	68.102, 93.997, 116.356
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	23
Space group name H-M	I222
Space group name Hall	I22
Symmetry operation	#1: x,y,z #2: x,-y,-z #3: -x,y,-z #4: -x,-y,z #5: x+1/2,y+1/2,z+1/2 #6: x+1/2,-y+1/2,-z+1/2 #7: -x+1/2,y+1/2,-z+1/2 #8: -x+1/2,-y+1/2,z+1/2

Components on special symmetry positions

ID	Model	Components
1	1	A-525- HOH
2	1	A-651- HOH
3	1	A-869- HOH

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Protein , 1 types, 1 molecules A

#1: Protein	S-adenosylmethionine synthase isoform type-2 / AdoMet synthase 2 / Methionine adenosyltransferase 2 / MAT 2 / Methionine adenosyltransferase II / MAT-II Mass: 43807.703 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MAT2A, AMS2, MATA2 / Production host: Escherichia coli (E. coli) / References: UniProt: P31153, methionine adenosyltransferase

#1: Protein

S-adenosylmethionine synthase isoform type-2 / AdoMet synthase 2 / Methionine adenosyltransferase 2 / MAT 2 / Methionine adenosyltransferase II / MAT-II

Mass: 43807.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: MAT2A, AMS2, MATA2 / Production host:

Escherichia coli (E. coli) / References: UniProt: P31153, methionine adenosyltransferase

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Non-polymers , 6 types, 787 molecules

#2: Chemical	ChemComp-SAM / S-ADENOSYLMETHIONINE Mass: 398.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₅H₂₂N₆O₅S
#3: Chemical	ChemComp-CL / CHLORIDE ION Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical	ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂H₆O₂
#5: Chemical	ChemComp-PEG / DI(HYDROXYETHYL)ETHER Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₄H₁₀O₃
#6: Chemical	ChemComp-7UB / (3'R)-2-[(cyclopropylmethyl)amino]-6-(4-methoxyphenyl)-1'-[(1H-pyrazol-5-yl)methyl]-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidin]-7-one Mass: 459.543 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₅H₂₉N₇O₂ / Feature type: SUBJECT OF INVESTIGATION
#7: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 778 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.13 Å³/Da / Density % sol: 42.13 %
Crystal grow	Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8 Details: 0.2 M LiCl, 0.1 M Tris pH 8.0, 16%-22% PEG6000, 10% Ethylene Glycol

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97853 Å
Detector	Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 2, 2016
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.97853 Å / Relative weight: 1
Reflection	Resolution: 1.19→50 Å / Num. obs: 117325 / % possible obs: 98.31 % / Redundancy: 3.7 % / B_iso Wilson estimate: 8.96 Å² / R_merge(I) obs: 0.239 / Net I/σ(I): 10.5
Reflection shell	Resolution: 1.19→1.23 Å / Redundancy: 3.5 % / R_merge(I) obs: 0.55 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 11605 / % possible all: 98.58

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Processing

Software

Name	Version	Classification
PHENIX	1.19.2_4158	refinement
HKL-2000		data reduction
HKL-2000		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 2P02

2p02

Resolution: 1.19→47 Å / SU ML: 0.1142 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 21.1873
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2

	R_factor	Num. reflection	% reflection
R_free	0.2356	5846	4.99 %
R_work	0.1992	111368	-
obs	0.201	117214	98.29 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Displacement parameters

B_iso mean: 14.71 Å²

Refinement step

Cycle: LAST / Resolution: 1.19→47 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2976	0	86	778	3840

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.0136	3264
X-RAY DIFFRACTION	f_angle_d	1.6705	4436
X-RAY DIFFRACTION	f_chiral_restr	0.1082	483
X-RAY DIFFRACTION	f_plane_restr	0.0111	578
X-RAY DIFFRACTION	f_dihedral_angle_d	19.7088	1259

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.19-1.2	0.2532	185	0.234	3561	X-RAY DIFFRACTION	95.66
1.2-1.22	0.2636	218	0.2237	3712	X-RAY DIFFRACTION	99.75
1.22-1.23	0.2534	201	0.2285	3701	X-RAY DIFFRACTION	99.72
1.23-1.25	0.2249	194	0.2176	3758	X-RAY DIFFRACTION	99.75
1.25-1.26	0.2329	211	0.2126	3737	X-RAY DIFFRACTION	99.62
1.26-1.28	0.2419	232	0.2115	3697	X-RAY DIFFRACTION	99.67
1.28-1.3	0.2416	196	0.2094	3712	X-RAY DIFFRACTION	99.52
1.3-1.32	0.2436	200	0.1998	3687	X-RAY DIFFRACTION	99.13
1.32-1.34	0.2377	202	0.1983	3709	X-RAY DIFFRACTION	99.04
1.34-1.36	0.2242	168	0.2012	3782	X-RAY DIFFRACTION	99.5
1.36-1.39	0.2145	200	0.1903	3735	X-RAY DIFFRACTION	99.72
1.39-1.41	0.2467	208	0.1945	3723	X-RAY DIFFRACTION	99.67
1.41-1.44	0.2253	203	0.1838	3737	X-RAY DIFFRACTION	99.49
1.44-1.47	0.2301	192	0.1868	3753	X-RAY DIFFRACTION	99.3
1.47-1.5	0.2116	164	0.1829	3709	X-RAY DIFFRACTION	99.08
1.5-1.53	0.2216	212	0.1798	3708	X-RAY DIFFRACTION	98.84
1.53-1.57	0.2001	186	0.1767	3751	X-RAY DIFFRACTION	99.04
1.57-1.61	0.2197	198	0.18	3728	X-RAY DIFFRACTION	99.32
1.61-1.66	0.2209	182	0.1776	3762	X-RAY DIFFRACTION	98.92
1.66-1.72	0.2172	210	0.1823	3728	X-RAY DIFFRACTION	99.39
1.72-1.78	0.2184	198	0.1837	3714	X-RAY DIFFRACTION	98.91
1.78-1.85	0.2264	187	0.1832	3723	X-RAY DIFFRACTION	98.27
1.85-1.93	0.2168	145	0.1893	3758	X-RAY DIFFRACTION	98.16
1.93-2.03	0.2332	185	0.1905	3716	X-RAY DIFFRACTION	97.82
2.03-2.16	0.2292	202	0.2009	3724	X-RAY DIFFRACTION	97.73
2.16-2.33	0.2209	204	0.2009	3679	X-RAY DIFFRACTION	97.03
2.33-2.56	0.2411	179	0.2081	3729	X-RAY DIFFRACTION	97.33
2.56-2.93	0.2576	193	0.2108	3633	X-RAY DIFFRACTION	94.63
2.93-3.7	0.2622	194	0.2029	3673	X-RAY DIFFRACTION	95.25
3.7-47	0.2435	197	0.2149	3629	X-RAY DIFFRACTION	90.32

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	0.686127343176	-0.113799170554	0.441014527423	0.46655260381	0.0610739095005	1.03902147299	-0.0410164422693	0.0339871538148	0.0444481530127	-0.0129264694714	0.0157021186014	-0.0202400936985	-0.0846109212998	0.0167164615453	0.0855202779332	0.0636383737125	-0.0102315864456	0.00496336429923	0.050554703836	0.00685910860461	0.0663481885943	5.48168146725	9.69218228577	-24.2078012369
2	0.444783430074	-0.394112712313	-0.315216312235	0.906765566233	0.165363711571	0.578030593979	-0.035314809903	-0.0147208120652	-0.0374630643444	0.0717613274972	0.0237287014288	-0.0464556390886	-0.00419494350948	0.0692259266837	0.00223719447684	0.0777850492297	0.00696929727328	-0.00398984832834	0.0787587373863	-0.0122640848182	0.0800244150837	12.353311203	0.525584996063	-9.11058172782
3	0.727892259233	-0.662652670315	0.107358974281	1.76652635644	-0.0550268245987	0.825999282685	-0.0477036934749	-0.015165007383	0.138454966543	0.0647011606318	0.0366581320271	-0.102352970999	-0.0427716782438	0.152361378509	-0.00482196201691	0.0932359797469	-0.0064792158993	-0.0113728150907	0.100382992311	-0.00260949303162	0.0859985322975	7.40101706285	15.9130002365	-5.62887623139
4	0.123185953781	-0.128233228754	0.00442053333833	0.468022195191	-0.0763978062463	0.268525485096	-0.000443927863531	0.00308563091036	0.0251042232389	-0.00603711025111	-0.0107277031446	-0.0539980783144	0.011090074604	0.0370554760818	0.0155377499061	0.0634912177062	-0.00738370283282	-0.000226649524139	0.081670354007	0.00404208618244	0.085995239205	11.8231120705	2.11681300898	-23.6695594037
5	0.484222581657	-0.176505303608	-0.0534369627126	0.871298468184	0.391866003464	0.892028462617	0.0183872468923	0.00805854759829	0.0838393677356	-0.0324662250762	-0.00704443391786	-0.00844266053886	-0.113231570796	-0.042803073243	-2.96711796904E-5	0.0687605704788	-0.000199933588642	-0.00153224981185	0.0631360097995	0.0123542491912	0.0839368458119	-3.68859969636	22.9900013631	-28.8786964521
6	0.808056896653	-0.0664603870284	-0.133321819557	0.689571747204	-0.295092455242	0.841995078302	0.00358600591156	0.0674941214986	0.101366006862	-0.0258468329417	0.0475738029977	0.0250636480719	-0.0944855137958	-0.054829269884	-0.057982876865	0.0761339021409	-0.00438038636009	-0.00124763940844	0.0512157331862	-0.00896121022189	0.0772165149004	-5.55474906379	22.0694654386	-26.8844732752
7	0.420763131839	-0.0985598202696	0.117226291033	0.225856604707	-0.114185061833	0.370753245638	0.00741349613674	0.0476431301666	0.0230522509525	-0.058020422031	-0.0112847172101	-0.0237540732049	-0.0147231465433	0.0523183863512	0.00737928788424	0.0779132054248	-0.00171597224542	0.00782954563636	0.0667300696497	0.00174584669971	0.069879411313	11.4570405061	-0.786738967397	-34.8857342341
8	1.38931354956	-0.473465704211	0.853459756607	0.855876214206	-0.675376491466	4.47904561335	0.0531657031617	0.167778635087	-0.066241242941	-0.16113743761	-0.0142409041043	-0.0451188740478	0.263978347651	0.103232635721	-0.0526790424564	0.101141264702	-0.00385006276485	0.0240956698373	0.0914944134233	0.00285716541007	0.114375483966	20.6702563489	-5.61376323753	-40.1053326201
9	0.938321953202	-0.019282611083	0.170025792568	0.897560203136	-0.125792146307	1.31481837034	0.00373363621086	0.0461560934448	0.120170820915	-0.0613296065485	-0.0220993260831	-0.114664079342	-0.126106178126	0.130968062555	-0.0123969143315	0.0782876372198	-0.0148820240196	0.00992944481082	0.0763249540394	0.00328679353399	0.0991447242537	18.8263604047	7.69803962524	-29.2824513037

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 13 through 48 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 49 through 78 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 79 through 104 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 105 through 169 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 170 through 224 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 225 through 262 )
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 263 through 341 )
8	X-RAY DIFFRACTION	8	chain 'A' and (resid 342 through 364 )
9	X-RAY DIFFRACTION	9	chain 'A' and (resid 365 through 395 )

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